Crystalline forms of n-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide

ABSTRACT

The present invention describes specific crystalline forms of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5 -yl)pyridine-3-carboxamide. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.

FIELD OF THE INVENTION

The present invention is directed to crystalline forms ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide,methods of making the same, pharmaceutical compositions comprising thesame and methods of treatment using the same.

BACKGROUND

Polymorphism denotes the existence of more than one crystalline form ofa substance. Polymorphs (or crystalline modifications) have an identicalchemical structure but often quite different physicochemical properties.Polymorphs include enantiotropic polymorphs and monotropic polymorphs.This ability of a chemical substance to crystallize in more than onecrystalline form can have a profound effect on the shelf life,solubility, formulation properties, and processing properties of a drug.In addition, the action of a drug can be affected by the polymorphism ofthe drug molecule. Different polymorphs can have different rates ofuptake in the body, leading to lower or higher biological activity thandesired. In extreme cases, an undesired polymorph can even showtoxicity. The occurrence of an unknown crystalline form duringmanufacture can have a significant impact.

Understanding and controlling polymorphism, then, gives a decidedadvantage in bringing new drugs to the marketplace. First and foremost,searching for any possible polymorphs for a drug product can be used todiminish the possibility of contamination during a drug's manufacture orstorage by other polymorphic forms. Failure to catch contamination canhave life-threatening consequences in some cases. Crystallizing anunintended polymorph during manufacture can mean weeks or even months ofproduction downtime while scientists find and correct the cause of thenew crystalline form or go through another round of testing to obtainapproval for the new crystalline form.

Second, understanding which crystalline forms of a drug are possible incertain cases allows researchers to maximize the desired properties of acompound, such as solubility, formulation properties, processingproperties, and shelf life. Understanding these factors early in thedevelopment of a new drug may mean a more active, more stable, or lessexpensively manufactured drug.

The compoundN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideof the formula

is a BCR-ABL tyrosine-kinase inhibitor. The compound of Formula (I),preparation of the compound of Formula (I), and pharmaceuticalcompositions of the compound of Formula (I) are originally described inWO 2013/171639 A1 as Example 9. The compound of Formula (I) is alsoknown as(R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide,or asciminib.

WO 2013/171639 A1 provides that the Compound of Formula (I) as useful intreating diseases which respond to inhibition of the tyrosine kinaseenzymatic activity of the Abelson protein (ABL1), the Abelson-relatedprotein (ABL2) and related chimeric proteins, in particular BCR-ABL1.While WO 2013/171639 Al describes a pharmaceutical compositioncomprising an amorphous dispersion ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide,it does not particularly disclose of any crystalline forms ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideor pharmaceutical formulations comprising the same.

Crystalline forms ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehave been discovered and exhibit new physical properties that may beexploited in order to obtain new pharmacological properties, and thatmay be utilized in the drug product development ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.

SUMMARY OF THE INVENTION

The present invention is directed to crystalline forms ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base.

The present invention is also directed to crystalline forms of thehydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.

The present invention also provides a pharmaceutical compositioncomprising: (a) a therapeutically effective amount of a crystalline formofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt thereof of the present invention; and(b) at least one pharmaceutically acceptable carrier.

The present invention is also directed to a method for treating anABL1/BCR-ABL1-mediated disorder comprising the step of administering toa subject in need of such treatment a therapeutically effective amountof a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt thereof of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the X-ray powder diffraction (XRPD) pattern forcrystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 2 depicts the differential scanning calorimetry curve forcrystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 3 depicts the thermogravimetric plot for crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 4 depicts the XRPD pattern for form S_(A) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 5 depicts the XRPD pattern for form S_(B) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 6 depicts the XRPD pattern for form S_(C) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 7 depicts the XRPD pattern for form S_(D) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base according to the present invention.

FIG. 8 depicts the XRPD pattern for crystalline form A of thehydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 9 depicts the differential scanning calorimetry curve forcrystalline form A of the hydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 10 depicts the thermogravimetric plot for crystalline form A of thehydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 11 depicts the XRPD pattern for crystalline form B of thehydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 12 depicts XRPD patterns for forms A and B of the hydrochloridesalt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 13 depicts XRPD pattern for form HA of the hydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideaccording to the present invention.

FIG. 14 depicts a flow diagram of the manufacturing process used for themanufacture of tablets comprising crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, the following definitions havethe indicated meaning, unless explicitly stated otherwise:

As used herein the term “room temperature” or “RT” refers to atemperature in the range of from 20 to 30° C.

The term “reflection” with regard to X-ray powder diffraction (XRPD) asused herein, means peaks in an X-ray diffractogram, which are caused atcertain diffraction angles (Bragg angles) by constructive interferencefrom X-rays scattered by parallel planes of atoms in solid material,which are distributed in an ordered and repetitive pattern in along-range positional order. Such a solid material is classified ascrystalline material, whereas amorphous material is defined as solidmaterial, which lacks long-range order and only displays short-rangeorder, thus resulting in broad scattering. According to literature,long-range order e.g. extends over approximately 100 to 1000 atoms,whereas short-range order is over a few atoms only (see “Fundamentals ofPowder Diffraction and Structural Characterization of Materials” byVitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers,2003, page 3).

The crystalline forms of the present invention may be referred to hereinas being characterized by graphical data “as shown in” a figure, forexample, XRPD. The person skilled in the art understands that factorssuch as variations in instrument type, response and variations in sampledirectionality, sample concentration and sample purity may lead to smallvariations for such data when presented in graphical form, for examplevariations relating to the exact peak positions and intensities.However, a comparison of the graphical data in the figures herein withthe graphical data generated for another or an unknown solid form andthe confirmation that two sets of graphical data relate to the samecrystal form is well within the knowledge of a person skilled in theart.

The terms “solid form” or “solid state form” as used hereininterchangeably refer to any crystalline and/or amorphous phase of acompound.

As used herein, the term “amorphous” refers to a solid form of acompound that is not crystalline. An amorphous compound possesses nolong-range order and does not display a definitive XRPD pattern withreflections.

As used herein the term “polymorph” refers to crystalline forms havingthe same chemical composition but different spatial arrangements of themolecules, atoms, and/or ions forming the crystal.

The term “hydrate” as used herein, refers to a crystalline solid whereeither water is cooperated in or accommodated by the crystal structure,e.g., is part of the crystal structure or entrapped into the crystal(water inclusions). Thereby, water can be present in a stoichiometric ornon-stoichiometric amount. When water is present in stoichiometricamount, the hydrate may be referred to by adding Greek numeral prefixes.For example, a hydrate may be referred to as a hemihydrate or as amonohydrate depending on the water/compound stoichiometry. The watercontent can be measured, for example, by Karl-Fischer-Coulometry.

The terms “dehydrating” or “dehydration” as used herein, describe the atleast partial removal of water from the crystal structure of the hostmolecule.

The term “solvate” as used herein, refers to a crystalline solid wereeither one or more organic solvent(s) is/are cooperated in oraccommodated by the crystal structure e.g. is/are part of the crystalstructure or entrapped into the crystal (water inclusions). Thereby, theone or more organic solvent(s) can be present in a stoichiometric ornon-stoichiometric amount. When the one or more organic solvent(s)is/are present in stoichiometric amount(s), the solvate may be referredto by adding Greek numeral prefixes. For example, a solvate may bereferred to as a hemisolvate or as a monosolvate depending on thesolvent(s)/compound stoichiometry. The solvent content can be measured,for example, by GC, NMR, SXRD and/or TGA/MS.

The term “pharmaceutically acceptable excipient” as used herein refersto substances, which do not show a significant pharmacological activityat the given dose and that are added to a pharmaceutical composition inaddition to the active pharmaceutical ingredient. Excipients may takethe function of vehicle, diluent, release agent, disintegrating agent,dissolution modifying agent, absorption enhancer, stabilizer or amanufacturing aid among others. Excipients may include fillers(diluents), binders, disintegrants, lubricants and glidants.

The terms “filler” or “diluent” as used herein refer to substances thatare used to dilute the active pharmaceutical ingredient prior todelivery. Diluents and fillers can also serve as stabilizers.

As used herein the term “binder” refers to substances that bind theactive pharmaceutical ingredient and pharmaceutically acceptableexcipient together to maintain cohesive and discrete portions.

The terms “disintegrant” or “disintegrating agent” as used herein refersto substances which, upon addition to a solid pharmaceuticalcomposition, facilitate its break-up or disintegration afteradministration and permits the release of the active pharmaceuticalingredient as efficiently as possible to allow for its rapiddissolution.

The term “lubricant” as used herein refers to substances that are addedto a powder blend to prevent the compacted powder mass from sticking tothe equipment during tableting or encapsulation process. They aid theejection of the tablet from the dies and can improve powder flow.

The term “glidant” as used herein refers to substances that are used fortablet and capsule formulations in order to improve flow propertiesduring tablet compression and to produce an anti-caking effect.

One aspect of the present invention provides distinct crystalline formsof the free base and the hydrochloride salt of the compoundN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.These “crystalline form(s)” (or “crystal forms” or “crystallinemodification(s)” or “polymorphic form(s)” or “polymorph(s)”, as theterms will be used interchangeably herein) differ with respect tothermodynamic stability, physical parameters, x-ray structure andmethods of preparation. Polymorphs exist in two main categories:enantiotropic or monotropic. “Enantiotropic” polymorphs are those thatcan interconvert depending upon the temperature at a given pressure ordepending upon the pressure at a given temperature, called thetransition temperature or pressure. The relative thermodynamic stabilityinverts above and below the transition temperature or pressure. If onepolymorph is more stable independent of the temperature, it is“monotropic.” While polymorphism classically refers to the ability of acompound to crystallize into more than one distinct crystal species(having identical chemical structure but quite different physicochemicalproperties), the term pseudopolymorphism is typically applied to solvateand hydrate crystalline forms. For purposes of this invention, however,both true polymorphs as well as pseudopolymorphs, i.e., hydrate andsolvate forms, are included in the scope of “crystalline forms.” Inaddition, “amorphous” refers to a disordered solid state. It should benoted that different samples of a particular crystalline form will sharethe same major X-ray powder diffraction (XRPD) “peaks” or “reflections,”but that there can be variation in powder patterns with regard to minorpeaks. In addition, the term “about” with regard to XRPD peak values (indegrees) generally means within 0.3°, more preferably within 0.2°, andmost preferably within 0.1° of the given value. Alternatively, the term“about” means (in this and all contexts) within an accepted standard oferror of the mean, when considered by one of ordinary skill in the art.As used herein, the term “substantially pure” means that more 50% of thecrystallineN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideor hydrochloride salt thereof is present in one of the forms describedherein and preferably at least 70%, more preferably at least 80%, andmost preferably at least 90% of one of the crystalline forms describedherein is present.

In one embodiment, a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideis provided, referred to as crystalline form A of the free base. Form Aof the free base is non-hygroscopic (exhibits less than 0.1% wateruptake at 25° C. up to 92% relative humidity) and has rather lowsolubility above pH 3. As measured on a VanKel instrument using a Cary100 photometer, the intrinsic dissolution rate of Form A was determinedin pH 4.5, pH 6.8 and 0.1 N HCl medium as follows:

TABLE 1 Results of Intrinsic Dissolution of Free Base form A Dissolutionmedium Intrinsic DR value [mg/min/cm2] HCL 0.1N 1.8; 1.9 Acetate bufferpH 4.5 n.a (does not dissolve) pH = 6.8 n.a (does not dissolve)

In one embodiment, the invention relates to crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidecharacterized by having a XRPD pattern comprising reflections at 2-Thetaangles (2 theta values) of:

-   12.7±0.2°, 18.9±0.2° and 20.8±0.2°; or-   12.7±0.2°, 15.3±0.2°, 18.9±0.2°, 20.8±0.2° and 25.0±0.2°; or-   5.8°±0.2°, 11.3°±0.2°, 11.6°±0.2°, 12.2°±0.2°, 12.7°±0.2°,    13.2°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 17.0°±0.2°, 17.4°±0.2°,    18.6°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 20.8°±0.2°,    21.8°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.0°±0.2°,    24.5°±0.2°, 25.0°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.1°±0.2°,    27.7°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.6°±0.2°, 30.2°±0.2°,    31.2°±0.2°, 32.0°±0.2°, 32.3°±0.2°, 32.8°±0.2°, 33.7°±0.2°,    34.5°±0.2°, 35.3°±0.2°, 37.0°±0.2°, 38.4°±0.2°, and 38.6°±0.2°, when    measured at a temperature in the range of from 20 to 25° C. with    Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

In another embodiment, crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideis characterized by having a XRPD pattern comprising at least three, orat least four, or at least five, or all, 2 theta values selected fromthe group consisting of 5.8°, 11.3°, 11.6°, 12.2°, 12.7°, 13.2°, 14.7°,15.3°, 17.0°, 17.4°, 18.6°, 18.9°, 19.4°, 19.8°, 20.8°, 21.8°, 22.2°,22.7°, 23.4°, 24.0°, 24.5°, 25.0°, 25.5°, 26.7°, 27.1°, 27.7°, 28.7°,29.3°, 29.6°, 30.2°, 31.2°, 32.0°, 32.3°, 32.8°, 33.7°, 34.5°, 35.3°,37.0°, 38.4°, and 38.6° (2θ degrees±0.2°), when measured at atemperature in the range of from 20 to 25° C. with Cu-Kalpha1,2radiation having a wavelength of 0.1541 Å.

In another embodiment of the present invention, crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base is characterized by the XRPD pattern of FIG. 1.

Thermal properties of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidewas analyzed by differential scanning calorimetry (DSC) at a scanningrate of 5° C./min. (FIG. 2) and thermogravimetric analysis (TGA) (FIG.3).

In addition, several solvates were discovered during equilibration,crystallization, andprecipitation studies of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.A methanol solvate form S_(A), a 1-propanol solvate form S_(B), and anethanol solvate form S_(C) was isolated during equilibration andcrystallization studies with the respective solvents. An acetone solvateform S_(D) from was isolated in a precipitation study with acetone andwater. Solvate forms S_(A), S_(B), S_(C), and S_(D) are characterized bythe XRPD patterns shown in FIGS. 4-7, respectively.

In another embodiment, the invention relates to crystalline forms of thehydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide,referred to as crystalline forms A and B and trihydrate, ModificationH_(A). Forms A and B are enantiotropically related. Form A possessesgreater physical stability at temperatures below the enantiotropictransition temperature range of 65° C. to 90° C. and Form B possessgreater physical stability above this range. Form B spontaneouslytransforms to Form A at ambient conditions. Form A can be converted toModification HA, or Form H_(A), when equilibrated in water at pH 1.

Form A of the hydrochloride salt is non-hygroscopic (exhibits less than0.4% water uptake at 25° C. up to 95% relative humidity) and has ratherlow solubility above pH 3. As measured on a VanKel instrument using aCary 100 photometer, the intrinsic dissolution rate of Form A wasdetermined in pH 3.5, pH 4.5 and 0.1 N HCl medium as follows:

TABLE 2 Results of Intrinsic Dissolution of form A of HCl saltDissolution medium Intrinsic DR value [mg/min/cm2] HCL 0.1N (pH 1) 0.16HCL 0.01N (pH 2) 2.25 Citrate buffer (pH 3.5) 0.02 Acetate buffer (pH4.5) 0.01

In another embodiment, the invention relates to crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride characterized by having a XRPD pattern comprisingreflections at 2-Theta angles (2 theta values) of:

-   12.6±0.2°, 18.9±0.2° and 20.9±0.2°; or-   12.6±0.2°, 17.0±0.2°, 18.9±0.2°, 20.9±0.2° and 32.5 ±0.2°; or-   8.5°±0.2°, 9.5°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.6°±0.2°,    13.9°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 17.0°±0.2°,    17.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.4°±0.2°,    20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.9°±0.2°,    24.3°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°,    27.0°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.8°±0.2°,    30.5°±0.2°, 31.3°±0.2°, 31.5°±0.2°, 31.8°±0.2°, 32.1°±0.2°,    32.5°±0.2°, 32.9°±0.2°, 33.6°±0.2°, 34.0°±0.2°, 34.6°±0.2°,    35.0°±0.2°, 35.6°±0.2°, 36.3°±0.2° and 38.8°±0.2°, when measured at    a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2    radiation having a wavelength of 0.1541 Å.

In another embodiment, the XRPD pattern of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by at least three, or at least four, orat least five, or all, 2 theta values selected from the group consistingof 8.5°, 9.5°, 11.8°, 12.3°, 12.6°, 13.9°, 14.8°, 15.9°, 16.5°, 17.0°,17.6°, 18.9°, 19.1°, 19.8°, 20.4°, 20.9°, 21.2°, 22.4°, 22.7°, 23.9°,24.3°, 24.8°, 25.0°, 25.9°, 26.8°, 27.0°, 28.3°, 28.6°, 28.9°, 29.8°,30.5°, 31.3°, 31.5°, 31.8°, 32.1°, 32.5°, 32.9°, 33.6°, 34.0°, 34.6°,35.0°, 35.6°, 36.3°, 38.8° (2θ degrees±0.2°, when measured at atemperature in the range of from 20 to 25° C. with Cu-Kalpha1,2radiation having a wavelength of 0.1541 Å.

In another embodiment of the present invention, crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by the XRPD pattern of FIGS. 8 and/or 12.

Thermal properties of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride was analyzed by differential scanning calorimetry (DSC) ata scanning rate of 2° C./min. (FIG. 9) and thermogravimetric analysis(TGA) (FIG. 10).

The XRPD pattern of crystalline form B ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by at least three, or at least four, orat least five, or all, 2 theta values selected from the group consistingof 8.5°, 8.6°, 9.2°, 10.8°, 11.8°, 12.7°, 13.8°, 14.7°, 15.6°, 14.8°,15.9°, 16.1°, 16.9°, 18.0°, 18.4°, 18.9°, 19.2°, 19.5°, 19.8°, 20.2°,20.4°, 20.8°, 20.9°, 21.1°, 21.6°, 21.9°, 22.3°, 22.6°, 23.1°, 23.4°,23.7°, 24.0°, 24.1°, 24.3°, 24.6°, 24.7°, 25.2°, 25.5°, 25.9°, 26.5°,27.0°, 27.6°, 28.4°, 28.5°, 28.9°, 29.5°, and 29.8° (2θ degrees±0.2°),when measured at a temperature in the range of from 100 to 125° C. withCu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

In another embodiment of the present invention, crystalline form B ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by the XRPD pattern of FIGS. 11 and/or12.

In another embodiment, the invention relates to crystalline trihydrateform H_(A) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride characterized by having a XRPD pattern comprisingreflections at 2-Theta angles (2 theta values) of:

-   10.4 ±0.2°, 21.8±0.2° and 30.6±0.2°, or-   10.4±0.2°, 12.0±0.2°, 16.8±0.2°, 21.8±0.2° and 30.6±0.2°, or-   7.9°±0.2°, 10.4°±0.2°, 12.0°±0.2°, 13.0°±0.2°, 13.3°±0.2°,    13.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 16.4°±0.2°, 16.8°±0.2°,    17.5°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 20.5°±0.2°, 20.8°±0.2°,    21.1°±0.2°, 21.8°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.0°±0.2°,    23.5°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 24.6°±0.2°, 25.0°±0.2°,    26.0°±0.2°, 26.3°±0.2°, 26.5°±0.2°, 26.8°±0.2°, 27.8°±0.2°,    28.2°±0.2°, 28.5°±0.2°, 28.8°±0.2°, 29.5°±0.2°, 30.0°±0.2°,    30.6°±0.2°, 31.0°±0.2°, 31.3°±0.2°, 31.7°±0.2°, 32.0°±0.2°,    33.2°±0.2°, 34.0°±0.2°, 34.2°±0.2°, 35.3°±0.2°, 35.9°±0.2°,    36.7°±0.2°, 37.0°±0.2°, 37.4°±0.2°, 37.7°±0.2°, 38.2°±0.2°,    28.9°±0.2° and 39.6°±0.2°, when measured at a temperature in the    range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a    wavelength of 0.1541 Å.

In another embodiment, the XRPD pattern of crystalline trihydrate formH_(A) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by at least three, or at least four, orat least five, or all, 2 theta values selected from the group consistingof 7.9°, 10.4°, 12.0°, 13.0°, 13.3°, 13.8°, 15.5°, 15.9°, 16.4°, 16.8°,17.5°, 19.7°, 20.1°, 20.5°, 20.8°, 21.1°, 21.8°, 22.2°, 22.7°, 23.0°,23.5°, 23.9°, 24.2°, 24.6°, 25.0°, 26.0°, 26.3°, 26.5°, 26.8°, 27.8°,28.2°, 28.5°, 28.8°, 29.5°, 30.0°, 30.6°, 31.0°, 31.3°, 31.7°, 32.0°,33.2°, 34.0°, 34.2°, 35.3°, 35.9°, 36.7°, 37.0°, 37.4°, 37.7°, 38.2°,38.9°, and 39.6° (2θ degrees±0.2°), when measured at a temperature inthe range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having awavelength of 0.1541 Å.

In another embodiment of the present invention, crystalline trihydrateform H_(A) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride is characterized by the XRPD pattern of FIG. 13.

Various methods can be used to achieve the crystalline forms of the freebase (forms A, S_(A), S_(B), S_(C), and S_(D)) and the hydrochloridesalt (forms A, B, and H_(A)) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.Such methods are as set forth above and as set forth in thebelow-presented examples and include equilibration with solvents,crystallization at room temperature, crystallization from hot saturatedsolutions, and precipitation by addition of solvent.

Another embodiment of the present invention is directed to apharmaceutical composition comprising:

-   -   (a) a therapeutically effective amount of a crystalline form of        N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide        free base or hydrochloride salt thereof according to one of the        earlier embodiments of the present invention; and        -   at least one pharmaceutically acceptable carrier, diluent,            vehicle or excipient.            In a preferred embodiment, the crystalline form is form A of            the hydrochloride salt of            N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.            Preferably, more than 50%, more preferably at least 70%,            still more preferably at least 80%, and most preferably at            least 90%, of the crystalline form present in the            composition is of one of the selected forms.

As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, e.g., those targeted for buccal,sublingual, and systemic absorption, boluses, powders, granules, pastesfor application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8)nasally; (9) pulmonary; or (10) intrathecally.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated, where more general terms wherever used may,independently of each other, be replaced by more specific definitions orremain, thus defining more detailed embodiments of the invention:

The term “disintegrant” means a substance that causes the tablet toexpand and dissolve when wet causing the tablet to break apart in thedigestive tract, releasing the active ingredient for absorption.Disintegrants ensure that when the tablet is in contact with water, itrapidly breaks down, facilitating dissolution. Disintegrants areselected from the group consisting of crosslinked polyvinylpyrrolidone(crospovidone), crosslinked sodium carboxymethyl cellulose, for example,croscarmellose sodium and sodium starch glycolate, preferably,croscarmellose sodium.

The term “filler”, also known as “diluent”, means an inert ingredientoften used in tablets and capsules to bulk up the content of the dosageform because the amount of active drug is too small to be handledconveniently (difficult to manufacture and handle). Examples offillers/diluents include, but are not limited to, starch, dextrin,sucrose, sorbitol, sodium saccharin, acesulfame potassium, xylitol,aspartame, mannitol, starch, PVP (polyvinyl pyrrolidone), low molecularweight HPC (hydroxypropyl cellulose), microcrystalline cellulose (MCC),low molecular weight HPMC (hydroxypropylmethylcellulose), low molecularweight carboxymethyl cellulose, ethyl-cellulose, dicalcium phosphate,silicified microcrystalline cellulose, alginates, gelatin, polyethyleneoxide, acacia, dextrin, sucrose, magnesium aluminum silicate,polymethacrylates, lactitol, lactose, suitable inorganic calcium salts,sucrose, glucose, mannitol, silicic acid, and any combination thereof.The fillers are an intra-granular component, comprising, by percentageweight, from about 60% to about 80%, based upon total weight of thetablet formulation.

The term “glidants” means a substance that is added to a powder toimprove the powder's ability to “flow” or flowability. Examples include,but are not limited to, magnesium stearate, sodium stearyl fumarate,talc, magnesium carbonate, fumed silica (silicon dioxide), silica,aerosol (colloidal anhydrous/colloidal silicon dioxide) and starch, orany combination thereof.

The term “lubricants” means a compound that acts to reduce friction byinterposing an intermediate layer between the tablet constituents andthe die wall during compression and ejection. Examples of lubricantsinclude, but are not limited to, stearates, sodium stearyl fumarate,magnesium salts, and magnesium stearate.

A “therapeutically effective amount” is intended to mean the amount ofthe inventive crystalline form that, when administered to a subject inneed thereof, is sufficient to effect treatment for disease conditionsalleviated by the inhibition of tyrosine kinase enzymatic activity ofthe Abelson protein (ABL1), the Abelson-related protein (ABL2) andrelated chimeric proteins, in particular BCR-ABL1. The amount of a givencompound of the invention that will be therapeutically effective willvary depending upon factors such as the disease condition and theseverity thereof, the identity of the subject in need thereof, etc.,which amount may be routinely determined by artisans of ordinary skillin the art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound that produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and acrystalline form of the present invention. In certain embodiments, anaforementioned formulation renders orally bioavailable an inventivecrystalline form of the present invention.

Methods of preparing these formulations or compositions include the stepof bringing into association an inventive crystalline form of thepresent invention with the carrier and, optionally, one or moreaccessory ingredients. In general, the formulations are prepared byuniformly and intimately bringing into association an inventivecrystalline form of the present invention with liquid carriers, orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution, suspension or solid dispersion in an aqueousor non-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion, or as an elixir or syrup, or as pastilles (using an inertbase, such as gelatin and glycerin, or sucrose and acacia) and/or asmouth washes and the like, each containing a predetermined amount of aninventive crystalline form of the present invention as an activeingredient. An inventive crystalline form of the present invention mayalso be administered as a bolus, electuary or paste.

The present invention also relates to a tablet formulation comprising acrystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt, and methods of use thereof.

In one embodiment, the tablet formulation provided herein can beformulated in a unit dosage form, each dosage containing from about 5 toabout 500 mg, of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt.

In a further embodiment, the unit dosage form contains between 10 mg and200 mg, of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt.

In a further embodiment, the unit dosage form contains between 25 mg and150 mg, inclusive, of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt.

In a further embodiment, the unit dosage form contains 20 mg, 40 mg, or60 mg of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt.

In another embodiment, the tablet formulation of the present inventioncomprises, by percentage weight: 10-30% of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt, 60-80% of one or more fillers, 2-10% ofone or more disintegrants; and 0.2-3% of one or more glidants.

In a further embodiment, the filler is one or more selected fromlactose, lactose anhydrous, lactose spray dried, directly compressiblestarch, hydrolyzed starch, MCC (Cellulose MK GR, Avicel PH 101), othercellulose derivatives (Natrium-CMC XL), dibasic calcium phosphatedihydrate, sorbitol, sucrose, calcium sulfate dehydrate and dextrose.

In a further embodiment, the disintegrant is one or more selected fromcrosslinked polyvinylpyrrolidone (crospovidone), hypromellose(low-substituted hydroxypropyl cellulose), crosslinked sodiumcarboxymethyl cellulose (croscarmellose sodium) and sodium starchglycolate.

In a further embodiment, the glidant is one or more selected frommagnesium stearate, sodium stearyl fumarate, magnesium carbonate, fumedsilica, silica, aerosol (colloidal anhydrous/colloidal silicon dioxide;Aerosil 200 PH) and starch.

In another embodiment, the tablet formulation of the present inventioncomprises an intra-granular phase, an extra-granular phase and afilm-coating.

In a further embodiment, the intra-granular phase comprises acrystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt, lactose, Avicel PH101, HP-Cellluloselow subst_40UM, Natrium-CMC XL, Aerosil 200 PH, and magnesium stearate.

In a further embodiment, the extra-granular phase comprises lactose,Cellulose MK GR, Natrium-CMC XL, Aerosil 200 PH, and magnesium stearate.

In a further embodiment, the tablet formulation of the present inventioncan be film-coated.

In a further embodiment, the film-coating can comprise one or morefilm-forming substances and can further comprise substances such asplasticizers, lubricants, colorants and/or pigments.

In a further embodiment, the film-coating comprises purified water and amixture of one or more coating premix selected from white, yellow, redand black.

In another embodiment, the intra-granular phase contains, by percentageweight: 22% of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride, 33% lactose, 17% Avicel PH 101, 5% HP-Celllulose lowsubst 40UM, 2% Natrium-CMC XL, 0.25% Aerosil 200 PH, and 0.50% magnesiumstearate.

In a further embodiment, the extra-granular phase contains, bypercentage weight: 10% lactose, 6% Cellulose MK GR, 3% Natrium-CMC XL,0.25% Aerosil 200 PH, and 1% magnesium stearate.

In a further embodiment, the film-coating contains, by percentageweight: 4.83% coating premix white; 0.16% coating premix yellow; 0.008%coating premix red and 85% purified water.

In a further embodiment, the film-coating contains, by percentageweight: 7.96% coating premix white; 0.019% coating premix red; 0.024%coating premix black and 85% purified water.

In a further embodiment, the tablet formulation comprises anintra-granular phase, an extra-granular phase and a film-coatingwherein: said intra-granular phase comprises the crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride, lactose, Avicel PH101, HP-Celllulose low subst 40UM,Natrium-CMC XL, Aerosil 200 PH, and magnesium stearate; saidextra-granular phase comprises lactose, Cellulose MK GR, Natrium-CMC XL,Aerosil 200 PH, and magnesium stearate; and said film-coating cancomprise one or more film-forming substances and can further comprisesubstances such as plasticizers, intestinal lubricants, colorants and/orpigments.

In a further embodiment, the tablet formulation comprises anintra-granular phase, an extra-granular phase and a film-coatingwherein: said intra-granular phase comprises, by percentage weight:about 22% of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride, about 33% lactose, about 17% Avicel PH 101, about 5%HP-Celllulose low subst 40UM, about 2% Natrium-CMC XL, about 0.25%Aerosil 200 PH, and about 0.50% magnesium stearate.

In a further embodiment, the extra-granular phase contains, bypercentage weight: about 10% lactose, about 6% Cellulose MK GR, about 3%Natrium-CMC XL, about 0.25% Aerosil 200 PH, about 1% magnesium stearate;and the film-coating contains, by percentage weight:

about 4.83% coating premix white; about 0.16% coating premix yellow;about 0.008% coating premix red and about 85% purified water.

In another embodiment, the extra-granular phase contains, by percentageweight: about 10% lactose, about 6% Cellulose MK GR, about 3%Natrium-CMC XL, about 0.25% Aerosil 200 PH, about 1% magnesium stearate;and the film-coating contains, by percentage weight: about 7.96% coatingpremix white; about 0.019% coating premix red; about 0.024% coatingpremix black and about 85% purified water.

The present invention also relates to a process for the production of atablet comprising a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt, wherein the process comprises:

-   -   (a) blending the intra-granular phase ingredients: crystalline        form A of        N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide        hydrochloride, Avicel PH101, HP-Celllulose low subst 40UM,        Natrium-CMC XL, Aerosil 200 PH and magnesium stearate;    -   (b) sieving, blending, roller compacting and milling the blended        ingredients from step (a);    -   (c) blending the extra-granular phase ingredients: lactose,        Cellulose MK GR, Natrium-CMC XL, Aerosil 200 PH and magnesium        stearate;    -   (d) sieving the ingredients from step (c);    -   (e) blending the ingredients from step (b) and step (d);    -   (f) compressing the ingredients of step (e) into tablets and        dedusting said tablets;    -   (g) forming a suspension of the film-coating: comprises purified        water and a mixture of one or more coating premix selected from        white, yellow, red and black; and    -   (h) film-coating the dedusted tablets of (f).

Another aspect of the present invention is directed to a method oftreating an ABL1/BCR-ABL1-mediated disorder comprising the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a crystalline form ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base or hydrochloride salt thereof according to one of the earlierembodiments of the present invention. In a preferred embodiment, thecrystalline form is form A of the hydrochloride salt ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.Preferably, more than 50%, more preferably at least 70%, still morepreferably at least 80%, and most preferably at least 90%, of thecrystalline form administered is of one of the inventive forms. As notedabove, illustrative modes of administration include oral, nasal,parenteral, topical, transdermal, and rectal. Administration of thecrystalline form may be accomplished by administration of apharmaceutical composition of this invention or via any other effectivemeans.

Specific embodiments of the invention will now be demonstrated byreference to the following examples. It should be understood that theseexamples are disclosed solely by way of illustrating the invention andshould not be taken in any way to limit the scope of the presentinvention.

EXAMPLES General Test Conditions

The following procedures were employed under each test condition.

Equilibration With Solvent at 25° C.

For equilibration at 25° C., about 50 mg of the drug substance wasequilibrated with 1 ml solvent for at least 1 week and about 4 weeks inEppendorf shaker at 25° C. ±0.5. The solutions were filtered and driedfor 10 minutes in the air. The solid part was investigated by XRPD(X-ray powder diffraction). If the information from XRPD wasinsufficient to evaluate the change, additional investigations by TG andNMR were performed.

Equilibration With Solvent at 50° C.

For equilibration with solvent at 50° C., about 50 mg of drug substancewas equilibrated with 1 ml solvent for 2 days in in Eppendorf shaker at50° C. ±0.1. The filtrate was investigated as noted above.

Crystallization at 25° C.

Combined with equilibrations, if solubility determined by gravimetry,the residue was examined for its polymorphic form.

Crystallization From Hot Saturated Solutions

For crystallization from hot saturated solutions, approximately 300 mgof drug substance was dissolved in the minimal amount of solvent at 60°C. and hot filtrated. No remaining crystals were visible. The solutionswere put in an ice bath and agitated. The precipitates were collected ona filter, dried and investigated as described in the equilibrationexample.

Precipitation by Addition of Solvent

For precipitation by addition of solvent, the drug substance wasdissolved in a solvent where the solubility is high and a solvent inwhich the substance is highly insoluble was added. The precipitate wastreated as described in the equilibration example.

X-Ray Diffraction

The X-ray powder diffraction (XRPD) patterns described herein wererecorded on a Bruker D8 Advance diffractometer using CuKa radiation. TheXRPD pattern was recorded between 2° and 40° (2-theta).

One of ordinary skill in the art will appreciate that an XRPD patternmay be obtained with a measurement error that is dependent upon themeasurement conditions employed. In particular, it is generally knownthat intensities in an XRPD pattern may fluctuate depending uponmeasurement conditions employed. It should be further understood thatrelative intensities may also vary depending upon experimentalconditions and wavelength of X-ray radiation used. The agreement in the2-theta-diffraction angles between specimen and reference is within 0.2°for the same crystal form and such degree of measurement error should betaken into account as pertaining to the aforementioned diffractionangles. Consequently, it is to be understood that the crystal forms ofthe instant invention are not limited to the crystal forms that provideX-ray diffraction patterns completely identical to the XRPD patternsdepicted in the accompanying Figures disclosed herein. Any crystal formsthat provide XRPD patterns substantially identical to those disclosed inthe accompanying Figures fall within the scope of the present invention.The ability to ascertain substantial identities of XRPD patterns iswithin the purview of one of ordinary skill in the art.

Thermogravimetric Method

The TGA instruments used to test the crystalline forms was a TA Q5000.Samples of 10 to 20 milligrams were analyzed at a heating rate of 20° C.per minute in the temperature range between 30° C. and about 300° C.

Differential Scanning Calorimetry (DSC)

The DSC instrument used to test the crystalline forms was a Mettler DSC1or a Perkin Elmer Diamond. The instrument was programmed to heat at 10°C. per minute in the temperature range between 30° C. and 300° C. undernitrogen flow at 30 mL/min.

Example 1 Preparation of Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideFree Base

N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide,the starting marterial, is prepared in accordance to Example 9 of WO2013/171639 A1. The starting material is suspended in methanol andheated at 30° C. to obtain a solution. Water is added to crystallize thefree base. The suspension is cooled to 10° C. and crystal form A of thefree base is isolated by filtration and drying.

The XRPD pattern for crystal form A of the free base is shown in FIG. 1.The differential scanning calorimetry curve of form A of the free baseshowed an onset of melting at about 194° C. followed by a peak at about198° C. as shown in FIG. 2. FIG. 3 depicts the thermogravimetric plotfor crystal form A of the free base. The single crystal data for crystalform A of the free base at 100K is as follows:

Molecular formula: C₂₀H₁₈ClF₂N₅O₃ Molecular weight: 449.84 Spacesymmetry monoclinic Space group C2 Cell Volume (Å³) 2001.0(8)  CrystalDensity (g/cm³) 1.493 a (Å) 14.422(3)  b (Å) 9.368(2) c (Å) 14.989(4) beta (°) 98.853(12) z 4

Example 2 Preparation of Form SA ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideFree Base

Methanol solvate form SA of the free base was obtained by equilibrationof crystal form A of the free base in methanol at 50° C. andcrystallization from hot saturated solutions of crystal form A of thefree base in methanol at 60° C. The XRPD pattern for crystal form SA ofthe free base is shown in FIG. 4.

Example 3 Preparation of Form S_(B) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideFree Base

1-propanol solvate form S_(B) of the free base was obtained byequilibration of crystal form A of the free base in 1-propanol at 25° C.(for 1 and 4 weeks) and at 50° C. as well as crystallization at 25° C.and hot saturated solutions at 60° C. in 1-propanol. The XRPD patternfor crystal form S_(B) of the free base is shown in FIG. 5.

Example 4 Preparation of Form S_(C) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideFree Base

Ethanol solvate form S_(C) of the free base was obtained byequilibration of crystal form A of the free base in ethanol at 50° C.and crystallization from hot saturated solutions at 60° C. in ethanol.The XRPD pattern for crystal form Sc of the free base is shown in FIG.6.

Example 5 Preparation of Form S_(D) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideFree Base

Acetone solvate form S_(D) of the free base was obtained byprecipitation by addition of solvent of crystal form A of the free basein acetone and water. The XRPD pattern for crystal form S_(D) of thefree base is shown in FIG. 7.

Example 6 Preparation of Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

Crystal form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base is suspended in methanol and hydrochloric acid is added. Thesuspension is heated to obtain a solution. Tert-butyl methyl ether(TBME) is added to form crystal form A of the hydrochloride salt. Thesuspension is cooled and crystal form A of the hydrochloride salt isisolated by filtration and drying.

Alternatively, crystal form A of the hydrochloride salt may also beisolated under the following conditions:

N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide(1 wt) is dissolved in methanol (8 wt) at 35° C. Hydrochloride acid(1.15 eq) is added to the solution to form crystal form A of thehydrochloride salt. The solution is heated to 50° C. Tert-butyl methylether (TBME) (5 wt) is added over 35 minutes. The solution is seededwith seeds of crystal form A of the hydrochloride salt (0.0009 wt)slurried in TBME (0.01 vol). The suspension is aged for 135 minutes.TBME (9.25 wt) is added over 1.5 hour. The slurry is cooled to IT=0° C.over 3 hours and held at 0° C. Afterwards the slurry is filtered and thecake is washed with methanol:TBME 1:9w/w (2V) and then with TBME (2V).The wet cake is dried under vacuum at 50° C. for 24 hours.

The XRPD pattern for crystal form A of the hydrochloride salt is shownin FIG. 8. The differential scanning calorimetry curve of form A of thehydrochloride salt depicts an endothermic event at about 90° C. as shownin FIG. 9. FIG. 10 depicts the thermogravimetric plot for crystal form Aof the hydrochloride salt. The single crystal data for crystal form A ofthe hydrochloride salt at 100K is as follows:

Space symmetry Triclinic Space group P1 Cell Volume (Å³) 1053.6(6) Crystal Density (g/cm³) 1.533 a (Å) 8.203(3) b (Å) 11.116(3)  c (Å)12.627(4)  beta (°) 97.711(12) Z 2

The single crystal data for crystal form A of the hydrochloride salt at298K is as follows:

Space symmetry Triclinic Space group P1 Cell Volume (Å³) 1082.9(6) Crystal Density (g/cm³) 1.491 a (Å) 8.245(3) b (Å) 11.352(4)  c (Å)12.697(4)  beta (°) 97.289(18) Z 2

Example 7 Preparation of Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride Seed Crystals

Crystal form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidefree base and hydrochloric acid are dissolved in isopropanol and heateduntil complete dissolution of the solids. The clear solution is allowedto equilibrate at RT and spontaneous crystallization in observed. Thesolid material is isolated, dried and analyzed by XRPD, NMR and HPLC.

Example 8 Preparation of Form B ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

Crystal forms A and B of the hydrochloride salt are enantiotropicallyrelated. Upon heating, crystal Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride spontaneously converts into

Form B. The phenomenon is fully reversible, providing that nodecomposition occurred (decomposition observed above 240° C.). Form Bspontaneously transforms back into Form A at ambient conditions. Whilethe transition temperature could not be determined accurately, a rangefrom 65° C. to 90° C. has been defined. Crystal form A of thehydrochloride salt is the thermodynamically stable form below thistransition temperature and crystal form B is the favored form above it.

The XRPD pattern for crystal form B of the hydrochloride salt is shownin FIG. 11. A superposition of XRPD patterns of crystal forms A and B ofthe hydrochloride salt is shown in FIG. 12. The single crystal data forcrystal form B of the hydrochloride salt at 363K is as follows:

Space symmetry Triclinic Space group P1 Cell Volume (Å³) 1114.6(15)Crystal Density (g/cm³) 1.449 a (Å) 9.957(8) b (Å) 10.461(8)  c (Å)11.146(8)  beta (°) 75.71(5) Z 2

Example 9 Thermodynamic Stability of Forms A and B ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

During thermal investigation, no melting point for either crystal formsA and B of the hydrochloride salt could be determined because form B wasfound to decompose prior to melting when heated up to 300° C.

The impact of the heating rate on transition temperature was evaluatedby heating and cooling cycles at different rates of 40, 20, 10, 5, 1 and0.5° C. per minute from -20° C. to 200° C. and then back to −20° C.Hermetically sealed, closed gold crucibles were used for all of thesemeasurements.

For each experiment (different heating rate), a fresh sample wasprepared. The observed transition temperatures are listed in Table 3.

TABLE 3 Transition Temperatures heating/cooling sample weight transitiontransition rate [mg] A → B B → A 40° C./min 3.077 103.7° C. 32.2° C. 20°C./min 3.396 104.8° C. 34.7° C. 10° C./min 3.400 102.1° C. 37.5° C.  5°C./min 7.005 100.3° C. 38.5° C.  1° C./min 8.994  96.5° C. 53.8° C. 0.5°C./min  8.331  95.1° C. 60.5° C.

Forms A and B are identified and confirmed by its corresponding XRPDpattern and thermal parameters.

Example 10 Preparation of Form H_(A) ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

When equilibrated in water, depending on pH, crystal form A of thehydrochloride salt, is either prone to disproportionate (pH>3.5) andrecrystallize out as crystal form A of the free base, remain stable, oris converting into the trihydrate H_(A) (pH 1). The XRPD pattern forcrystal form H_(A) of the free base is shown in FIG. 13.

Example 11 Tablet Formulation Comprising Crystalline Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

A number of trials were undertaken to develop a suitable formulation ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidethat allows for reasonable dose strength with immediate releaseproperties and acceptable size, favorable dissolution profile, andeconomical manufacturing process. Crystal form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride film coated tablets was discovered to exhibit advantageouspharmacological properties for drug development.

20 mg and 40 mg Tablet Formulation 20 mg API 40 mg API CompositionComposition Composition per unit per unit Component (%) (mg/unit)(mg/unit) Internal Compound 1^(1,2) 21.62 21.62 43.24 Phase Lactose²32.91 32.91 65.82 Avicel PH 101² 17.72 17.72 35.44 HP-Cellulose Low 5.005.00 10.00 Subst_40UM.001 Natrium-CMC XL 2.00 2.00 4.00 Aerosil 200PH0.25 0.25 0.50 Magnesium 0.50 0.50 1.00 Stearate External Lactose 10.2010.20 20.40 Phase Cellulose MK GR 5.55 5.55 11.10 Natrium-CMC XL 3.003.00 6.00 Aerosil 200PH 0.25 0.25 0.50 Magnesium 1.00 1.00 2.00 stearateTotal 100.00 100.00 200.00 Core Tablet Coating Premix 4.832 7.957 WhiteFMP Coating Premix 0.160 Yellow FMP Coating Premix 0.008 0.019 Red FMPCoating Premix 0.024 Black FMP Water purified³ Total 105.0 208.0 withCoating ¹Compound 1 is active product ingredient (API) crystal form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride. ²Excess quantity is taken to compensate any drugsubstance potency below 100%. ³Removed during processing.

Example 12 Manufacturing Process for Film Coated Tablets ComprisingCrystal Form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride

The process described below may be reasonably adjusted, whilemaintaining the same basic production steps, to compensate for differentbatch sizes and/or equipment characteristics, and/or on the basis ofexperience:

The core tablet manufacture consists of standard mixing, sieving, drygranulation, tableting and film coating steps. The procedure is asfollows:

Step 1: All components of the internal phase were mixed in the followingorder: lactose, Compound 1, Natrium-CMC XL, Aerosil 200 PH,HP-Celllulose low subst_40UM and Avicel PH101 into a suitable container.The mixture was blended in a diffusion mixer.

Step 2: The blend from step 1 was screened using a screening mill fittedwith 0.800 mm hand sieve or oscillating mill. The mixture was furtherblended in a diffusion mixer with magnesium stearate.

Step 3: The blend from step 2 is compacted using a roller compactor andmilled using a screening mill fitted with 0.8 mm screen.

Step 4: The external phase excipients were loaded into a suitableblending bin in the following order: Lactose, Natrium-CMC XL, Aerosil200 PH and Cellulose MK GR after being screened using a screening millfitted with 0.800 mm hand sieve or oscillating mill. The mixture wasblended with the blend from Step 3 in a diffusion mixer.

Step 5: The mixture from blend from step 4 was further blended in adiffusion mixer with magnesium stearate.

Step 6: The mixture from step 5 was compressed into tablets using arotary tableting machine. The core tablets were dedusted and checkedform metal.

Step 7: Coating premixes and purified water were mixed to form a coatingsuspension that was used to film-coat the dedusted tablets of step 6 ina perforated pan coater.

An illustration of this process is found in FIG. 14.

Example 13 Pharmacokinetic Study

A dog study was conducted with capsule formulations of a solid amorphousdispersion ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideand of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamideto demonstrate the food effect prediction in humans. The mean ±SDpharmacokinetic parameters of the solid dispersion formulation and thecrystalline formulation were evaluated in plasma of dog model (n=3) pergroup following oral administration of 150 mg dose, fasted overnightbefore the dose and for 2 hours post-dose, under fast and fed state toobserve fed impact on absorption. Serial blood samples were collectedfrom each animal pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 24, 30, and 48 hpost-dose.

TABLE 4 Study Summary and mean ± SD pharmacokinetic parameters SolidSolid dispersion dispersion Crystalline Crystalline Formulation/formulation formulation w/ formulation formulation w/ Treatment w/o mealmeal w/o meal meal Tmax (h) * 2.0 (2.0-2.0) 3.3 (2.0-4.0) 2.0 (1.0-4.0)3.3 (2.0-4.0) Cmax 5600 ± 3880 ± 2900 ± 3080 ± (ng/mL) 2520 764 1690 857Apparent 3.29 ± 3.68 ± 3.25 ± 3.4 ± T1/2 (h) 0.135 0.163 0.115 0.0791AUC0-48 h 41300 ± 32000 ± 10300 ± 26000 ± (ng · h/mL) 18200 7920 15208450 AUCinf 41400 ± 32100 ± 11200 ± 26100 ± (ng · h/mL) 18200 7930 29908600 * Tmax given as mean and range

The food effect is formulation dependent. The following observationswere made:

1. For the crystalline formulation, there was 133% (AUCinf, 26100 vs11200 ng·h/mL) increase of exposure after dosing with meal compared withthat without a meal (positive food effect).

2. For the solid dispersion formulation, there was 22.5% (AUCinf, 41400vs 32100 ng·h/mL) decrease of exposure after dosing with a meal comparedwith that without a meal (negative food effect).

3. Under fasting conditions, there was a 3.7-fold higher exposure(AUCinf, 41400 vs 11200 ng·h/mL) with the solid dispersion formulationas compared to the crystalline formulation.

Example 14 Pharmacokinetic Study

A dog study was conducted with a formulation of crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride to demonstrate the food effect prediction in humans.

The mean±SD pharmacokinetic parameters of the formulation was evaluatedin plasma of dog model (n=3) following oral administration of 150 mg,fasted for approximately 18 hours, and fed 2 hours after dosing, toobserve fed impact on absorption. Serial blood samples were collectedfrom each animal pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 24, 30, and 48 hpost-dose.

TABLE 5 Study Summary and mean ± SD pharmacokinetic parametersFormulation/Treatment HCl salt formulation Tmax (h) * 3.3 (2-4) Cmax(ng/mL) 6540 ± 920 Apparent T1/2 (h)  5.0 ± 1.4 AUC0-48 h(ng · h/mL)51600 ± 7060 AUCinf (ng · h/mL) 51800 ± 7180 AUCinf/dose (ng · h/mL)/mg3450 ± 479 * Tmax given as mean and range

The following observations were made:

1. There was a 1.6-fold higher exposure (AUCinf, 51800 vs 32000 ng·h/mL)with hydrochloride salt formulation as compared with the soliddispersion formulation taken without a meal.

2. The hydrochloride salt formulation and the solid dispersionformulation are expected to provide comparable bioavailability inhumans.

1. A crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxpyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyridine-3-carboxamidehydrochloride.
 2. The crystalline form according to claim 1characterized by having an x-ray powder diffraction pattern comprisingreflections at 2-Theta angles of 12.6±0.2°, 18.9 ±0.2° and 20.9 ±0.2°,when measured at a temperature in the range of from 20 to 25° C. withCu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.
 3. Thecrystalline form according to claim 1 characterized by having an x-raypowder diffraction pattern comprising reflections at 2-Theta angles of12.6±0.2°, 17.0±0.2°, 18.9 ±0.2°, 20.9 ±0.2° and 32.5 ±0.2°, whenmeasured at a temperature in the range of from 20 to 25° C. withCu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.
 4. Thecrystalline form according to claim 1 characterized by having an x-raypowder diffraction pattern comprising three, four, five or more 2 thetavalues selected from the group consisting of 8.5°±0.2°, 9.5°±0.2°,11.8°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.9°±0.2°,16.5°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°,20.4°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.9°±0.2°,24.3°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.0°±0.2°,28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.8°±0.2°, 30.5°±0.2°, 31.3°±0.2°,31.5°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 32.5°±0.2°, 32.9°±0.2°, 33.6°±0.2°,34.0°±0.2°, 34.6°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 36.3°±0.2° and38.8°±0.2°, when measured at a temperature in the range of from 20 to25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å. 5.(canceled)
 6. The crystalline form according to claim 1 characterized byhaving a differential scanning calorimetry curve comprising anendothermic peak having an onset temperature of 90° C., when measured ata heating rate of 2° C./min.
 7. The crystalline form according to claim1 characterized by having a thermogravimetric analysis curve showing amass loss of not more than 3.3 weight % based on the weight of thecrystalline form, when heated from 30 to 300° C. at a rate of 20°C./min. 8-47. (canceled)
 48. A method for treating anABL1/BCR-ABL1-mediated disorder, comprising administering to a patientin need of such treatment an effective amount of a crystalline form A ofN-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamidehydrochloride according to claim
 1. 49. The method for treating anABL1/BCR-ABL1-mediated disorder according to claim 48 wherein theABL1/BCR-ABL1-mediated disorder is chronic myeloid leukemia.